The novel halogenating agent and halogenating method of the invention enable high purity and high yield production of halogenated aromatic compounds, halogenated heterocyclic compounds and halogenated cholesterol derivatives, each being useful for an intermediate for medicine and agricultural chemical, and also 7-acylamide-3-halocephem derivative useful for general cephem antibiotics used by oral administration.
As a method of halogenating hydroxyl group, it has been conventionally proposed to employ for example dimethyl haloiminium compound and diphenyl haloiminium compound, as a halogenating agent.
More specifically, Journal of Synthetic Organic Chemistry, 1980, 746 discloses a method in which dimethylformamide is reacted with oxalyl dichloride to obtain dimethyl chloroiminium compound, and hydroxyl group bonded to a straight-chain alkyl group is chlorinated by using the above chloroiminium compound. With this method, a 90% yield is achieved, however, such a high yield is not always obtained. Also, the purity of the resulting halogenide is about 80% at the most, and the reaction time is extremely long, namely, 24 hours.
Journal of the Pharmaceutical Society of Japan 85(6), 544-546 (1965) describes a method in which dimethylformamide is reacted with thionyl chloride to form dimethyl chloroiminium compound, and phenolic hydroxyl group is chlorinated by using this compound. This method, however, has the drawbacks that it is not applicable to a compound which has on its benzene ring a substituent liable to be chlorinated, except for hydroxyl group, and that since the reaction system becomes strongly acidic condition, application is limited to one which can be separated outside of the system, as a crystal, immediately after the termination of the reaction, thus being impractical.
Dimethyl haloiminium compound is also used in preparing N-acyl-4-chloro-1,2-dihydropyridine which is an intermediate for alkaloid [J. Org. Chem. (1993) 58, 7732-7739]. This method is, however, impractical because the reaction time is markedly long, namely, three days.
Further, it has been proposed to use dimethyl haloiminium compound in producing a 3-halogenated cephem derivative which is an intermediate for cephalosporin antibiotic used by oral administration (JP-A-116095/1974) With this method, however, the yield is as low as about 60% because the 7-position acyl group is also chlorinated, in addition to the desired 3-position hydroxyl group.
In the meantime, it is known a method with which the hydroxyl group bonded to a straight-chain alkyl group, the hydroxyl group bonded to a straight-chain alkenyl group, and the hydroxyl group of cholesterol, are chlorinated by using diphenyl chloroiminium chloride [Chemistry Letters, pp1173-1174 (1984)]. This method, however, fails to overcome the drawbacks that the reaction time is long, the purity of the resulting halogenide is low, and high yield is not ensured. Furthermore, this method is unsatisfactory for industrial production because the yield does not exceed 90% when chlorinating cholesterol or the compounds containing a double bond or ether linkage within the straight-chain molecules.
An object of the invention is to overcome the drawbacks of long reaction time, unstable yield, low purity, and the formation of by-product obtained by halogenation of other than the desired hydroxyl group, which drawbacks being common to the methods of halogenating hydroxyl group by using dimethyl haloiminium compound or diphenyl haloiminium compound.